Cytomegalovirus (CMV) is the most common cause of congenital infection in the United States, infecting approximately 2% of all newborns. Only a small proportion of this group presents with classical cytomegalle inclusion disease (CID) characterized by hepatosplenomegaly, jaundice, microcephaly, motor abnormalities, and mental retardation. Another group of infants, although uninfected at birth, develop CMV infection within the first three months of life, probably as a result of passage through an infected birth canal. The majority of these infants do not become clinically ill, but a few develop significant pulmonary disease. The extremely important question of why only some infants of infected mothers develop congenital or acquired infections and why only a portion of infected infants develop disease has not been answered. In recent years, many associations between antigens of the major histocompatibility (HLA) system and specific diseases have been reported. We propose to utilize our well defined populations of children and mothers from our CMV studies to determine if any host factors can be detected by HLA and/or erythrocyte antigen typing as well as by maternal HLA antibody screening which would help to explain the variety of pathogenic responses to CMV infection. The close proximity of the histocompatibility genes to genes influencing immune response, several components of the complement system, and at least one factor of the properdin system strongly suggests that this approach may prove fruitful. These studies should provide a back round for further investigation of CMV pathogenicity, particularly the role of host response.